N-(furyl- or thienyl-methyl)-14-oxy-7,8-dihydro-normorphinones and -norcodeinones and salts thereof

ABSTRACT

Compounds of the formula   WHEREIN R1 is hydrogen, methyl or acetyl, R2 is hydrogen or acetyl, R3 is hydrogen or methyl, Q is oxygen, dimethoxy, diethoxy, ethylene-dioxy or propylene(1,3)dioxy, and X is oxygen or sulfur, AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS OPIATE-ANTAGONISTS.

finite Merz et al.

States Patent [191 Mar. 18, 1975 N-(FURYL- ()R THlENYL-METHYL)-l4-()XY-7,8- DlHYDRO-NORMORPHINONES AND -NORCODEINONES AND SALTS THEREOF [75] Inventors: Herbert Merz; Adolf Langbein;

[2]] Appl. No.: 386,065

[30] Foreign Application Priority Data Aug. 7, 1972 Germany 2238839 [52] US. Cl. 260/285, 424/260 [51] Int. Cl C07d 43/28 [58] Field of Search 260/285 [56] References Cited v UNITED STATES PATENTS 3,793329 2/1974 Merz et all 260/285 Primary E.\'anzinerAlton D. Rollins Assistant E.\'aminer--Mary C. Vaughn Attorney, Agent, or Firml-lammond & Littell [57] ABSTRACT Compounds of the formula N-CHZ4& $11

wherein R is hydrogen, methyl or acetyl.

R is hydrogen or acetyl,

R is hydrogen or methyl Q is oxygen, dimethoxy. diethoxy. ethylenc-dioxy or propylene( 1,3)dioxy. and

X is oxygen or sulfur,

and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as opiate-antagonists.

10 Claims, N0 Drawings N-(FURYL- OR H EPLYLME HY ):I4- X -LQQIHYDRQ; I NORMORPHINONES AND -NORCODEINONES AND SALTS THEREOF This invention relates to novel N-(furylor theinylmethyl)-l4-0Xy-7,8-dihydro-normophinones and -norcodeinones and non-toxic acid addition salts thereof, as well as to various methods for preparing these compounds.

More particularly, the present invention relates to a novel class of normorphinones and norcodeinones represented by the formula of the formula --N-cH, R3 R2 l R1 0 O wherein R R R and X have the same meanings as in formula I, and non-toxic, pharmacologically acceptable acid addition salts thereof.

A further subgenus thereunder is constituted by compounds of the formula wherein R and X have the same meanings as in formula I.

Finally, an especially preferred subgenus thereunder is constituted by compounds of the formula HO s) wherein R has the same meanings as in formula I.

The compounds embraced by formula I may be prepared by a number of different methods among which the following have proved to be particularly convenient and efficient: Method A By alkylating a normorphinone or norcodeinone of the formula wherein R R and O have the same meanings as in formula I, with a furylor thienyl-methyl compound of the formula Y-CHPE j z wherein R and X have the same meanings as in formula I, and Y is halogen (preferably chlorine, bromine or iodine), arylsulfonyloxy, aralkylsulfonyloxy, alkylsulfonyloxy or any other readily anionically removable substituent.

The reaction is performed with the stoichiometric amount or a slight excess thereover of the alkylating agent of the formula III, and advantageously in the presence of an acid-binding agent, such as triethylamine, N,N-dicyclohexylethylamine, sodium carbonate, potassium carbonate, calcium oxide or preferably sodium bicarbonate. It is advantageous to perform the reaction in an inert organic solvent medium, such as chloroform, methylene chloride, benzene, acetone, dioxane, tetrahydrofuran, dimethylformamide or mixtures of any two or more of these, especially mixtures of dimethylformamide and tetrahydrofuran. The reaction temperature may be varied within wide limits, although temperatures between 0 C and the boiling point of the particular solvent which is used are preferred.

(III) in the presence of formaldehyde.

The reaction is carried out in acid solution, especially in weakly acid solution and preferably in acetic acid solution, the solvent medium being water, a lower alkanol, tetrahydrofuran, dioxane or mixtures of any two or more or these. The formaldehyde may be provided in stoichiometric amount or in slight excess thereover, either as such or in the form of paraformaldehyde, or more preferably in aqueous solution (formalin). The furan reactant of the formula IV is provided in the stoichiometric amount or in slight excess thereover. The reaction temperature may be varied with the range of 0 C and the boiling point of the particular solvent medium which is used, but a temperature between and 40 C is preferred.

After completion of the reaction, the desired reaction product is isolated, purified and crystallized by conventional procedures.

Method C By reducing a carboxylic acid amide or thioamide of the formula N LHR.

OR 2 X wherein R R R3, Q and X have the same meanings as in formula I, and Z is oxygen or sulfur.

The reduction of a carboxylic acid amide of the formula V (Z oxygen) may be effected by various known methods, among which the reduction with a complex hydride, especially with lithium aluminum hydride, is particularly preferred. However, this reduction can be applied only to those carboxylic acid amides of the formula V wherein Q is other than oxygen. The complex hydride is provided in the stoichiometric amount or in excess thereover, preferably up to twice the calculated amount. The reduction is advantageously performed in an inert organic solvent medium, such as diethyl ether, diisopropyl ether or especially tetrahydrofuran, The reaction temperature may be varied within wide limits, but the preferred range is between 0 C and the boiling point of the particular solvent which is used.

The reduction of a thioamide of the formula V (Z sulfur) may be effected with a complex hydride; with nascent hydrogen generated in situ by zinc/acetic acid or aluminum amalgam/water, for example; by catalytic hydrogenation in the presence of Raney nickel; or by electro-chemical reduction. The limitation regarding the meaning ofQ set forth above in connection with the carboxylic acid amides of the formula V does not apply to the thiomides.

After completion of the reduction, the desired end product is isolated, purified andcrystallized by conventional procedures.

Method D by cleavage of a functional oxo-group derivative of the formula W R/ ill gig wherein R R R and X have the same meanings as in formula I, and D is =NOH, =NNH =N-N- HCONH ,'=NNH(C=NH)NH two monovalent oxyalkyl groups (ketal grouping) or a dioxyalkylene group (cycloketal grouping).

The cleavage is effected by hydrolysis in an acid medium pursuant to known methods, andthe reaction product is isolated, purified and crystallized by conventional procedures.

Method E For the preparation of a compound of the formula I wherein Q is other than oxygen, by ketalization of a compound of the formula la.

The reaction is carried out pursuant to known methods. For instance, the ketone of the formula la is reacted with the desired hydroxy compound in the presence of an acid catalyst, such as p-toluenesulfonic acid, concentrated sulfuric acid, perchloric acid, aluminum chloride or borontrifluoride, ina suitable solvent medium. The hydroxy compound is advantageously provided in excess over the calculated amount, and a sufficiently large excess may serve as the solvent medium for the ketalization reaction. The water released by the reaction may be continuously removed during the reaction in vacuo or by azeotropic distillation. It is of advantage to employ a ketalization agent, such as an orthoformate, a sulfurous acid ester, a silicate or the like.

After completion of the reaction, the desired end product is isolated, purified and crystallized by conventional procedures.

Method F For the preparation of a compound of the formula I wherein R and R are acetyl, by acetylating a compound of the formula I wherein R, and/or R are hydrogen.

The acetylation is effected by known methods with conventional acetylating agents, such as acetic acid anhydride, acetyl chloride or ketene. It may be carried out in a suitable inert solvent medium, such as pyridine, or also without a separate solvent, especially when acetic acid anhydride is used, provided a sufficient excess of the acetylating agent is supplied.

After completion of the reaction, the desired end product is isolated, purified and crystallized by conventional procedures.

The starting compounds required for methods A to E are either known compounds or may be prepared by known methods.

For instance, the compounds of the formula 11, wherein R is hydrogen or methyl, R is hydrogen and Q is oxygen, are described in the literature [see Takamine Kenkyusko Nempo 12, 56-62 (1960); and CA. 55, 8449 d, e and f].

A compound of the formula 11 wherein R, and/or R are acetyl may be obtained, for example, by N- benzylation, followed by acetylation, and subsequent removal of the Nbenzyl protective group by catalytic hydrogenation.

A compound of the formula II or VI wherein Q and D, respectively, are ketal groupings may be obtained by ketalization of a corresponding oxo-compound (Q or D oxygen) in analogy to method E.

An amide or thioamide of the formula V may be obtained in conventional fashion by N-acylation of the corresponding nor-compound, as illustrated in Examples 12-20 below.

A compound of the formula VI, wherein D is other than a ketal or cycloketal grouping, may be obtained by conventional methods, such as by oximation or the like, from the corresponding ketone (D oxygen).

The compounds embraced by formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, hy-

droiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, caproic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, phthalic acid, cinnamic acid, salicyclic acid, ascorbic acid, 8-chlorotheophylline, methanesulfonic acid or the like.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 N-Furfuryl- 1 4-hydroxy-7,8-dihydro-normorphinone and its hydrochloride by method A A mixture consisting of 6.26 gm (0.02 mol) of 14- hydroxy-7,8-dihydro-normorphinone hydrochloride, 60 ml ofdimethylformamide, ml of tetrahydrofuran, 4.2 gm of sodium bicarbonate and 2.6 gm (0.022 mol) of furfuryl chloride was refluxed for 4 hours. Thereafter, the reaction solution was evaporated in vacuo, and the residue was shaken with a mixture consisting of 50 ml of chloroform and 50 ml of water. The aqueous phase was separated and extracted twice with 25 ml of chloroform, the extracts were combined with the organic phase, and the combined chloroform solutions were washed with water, dried with sodium sulfate and evaporated in vacuo.

The residue consisted of raw N-furfuryll4-hydroxy- 7,8dihydro-normorphinonc, which was dissolved in 50 ml of chloroform.

' furfuryl-l4-hydroxy-7,8-dihydronormorphinone a. 25 ml of the chloroform solution of the raw base were poured into a colume of 40 gm of aluminum oxide which had a metling point of 240C. A sample recrystallized from ethyl acetate had a melting point of 241C.

b. The other 25 ml of the chloroform solution of the raw base were introduced into a silicagel column prepared with 250 gm of silicagel and a flow agent consisting of chloroform/methanol/concentrated ammonia in the ratio 90:10:05. The column was eluted with the indicated flow agent, and the eluate was collected in fractions of 25 ml each. The fractions were thin-layerchromatographically tested for content of pure base, those fractions containing the pure base were combined, and the combined fractions were evaporated in vacuo. The residue was dissolved in a little ethanol in the presence of 4.0 ml of 2.5 N ethanolic hydrochloric acid, and the resulting solution was admixed with absolute ether until it just began to turn cloudy. The mixture was allowed to stand overnight in a refrigerator, and the precipitate formed thereby was collected by vacuum filtration, washed first with ethanol/ether (1:1) and then only with ether, and dried at C, yielding 2.5 gm (61.5 percent) of theory) of crystalline N- hydrochloride having a melting point of 230C which did not change after recrystallization from ethanol/ether.

EXAMPLE 2 N-Thenyl-l4-hydroxy-7,S-dihydro-normorphinone and its hydrochloride by method A A mixture consisting of 3.24 gm (0.01 mol) of 14- hydroxy-7,8-dihydro-normorphinone hydrochloride, 1.45 gm (0.011 mol) of thenyl chloride, 2.1 gm of sodium bicarbonate and 50 ml of diemethylformamide was stirred at 60 C for 5 hours. Thereafter, the reaction solution was evaporated in vacuo, and the residue was shaken with a mixture consisting of 50 m1 of ch10 reform and 50 ml ofwater. The aqueous phase was separated and extracted twice with 25 ml of chloroform each, the extracts were combined with the chloroform phase, and the combined chloroformic solutions were washed with water, dried with sodium sulfate and evaporated in vacuo. The residue, the free base N-thenyll4-hydroxy-7,8-dihydronormorphinone, was dissolved in a little ethanol by adding 4.0 ml of 2.5 N ethanolic .1 QT W which had a melting point of 29029 1 C. Recrystallization from ethanol/ether did not change the melting point.

EXAMPLE 3 Using a procedure analogous to that described in Example 2, 2.9 gm (69 percent of theory) of N-3-thienylmethyl)-l4-hydroxy-7,8-dihydro-normorphinone hydrochloride, m.p. 319 C, were obtained from 3.24 gm (0.01 mol) of l4-hydroxy-7,8-dihydro-normorphinone hydrochloride and 1.95 gm (0.011 mol) of S-bromomethyl-thiophene.

EXAMPLE 4 Using a procedure analogous to that described in Example 2, 3.7 gm (88.5 percent of theory) of N-furfuryl- 14-hydroxy-7,S-dihydro-norcodeinone hydrochloride, m.p. 241 C, of the formula N-CH: I i OH O were obtained from 3.37 gm (0.01 mol) of 14-hydroxy- 7,8-dihydro-norcodeinone hydrochloride and 1.26 gm (0.011 mol) of furfuryl chloride.

After recrystallization from ethanol/ether the prod uct had a melting point of 243 C.

EXAMPLE 5 Using a procedure analogous to that described in Example 2, 3.1 gm (74 percent of theory) of N-(3-furylmethyl)-14-hydroxy7,8-dihydro-norcodeinone hydrochloride, m.p. 265 C, were obtained from 3.37 gm (0.01 mol) of 14-hydroxy-7,S-dihydro-norcodeinone hydrochloride and 1.26 gm (0.011 mol) of 3- chloromethyl-furan with a mixture of ml of dimethylformamide and I 15 ml of tetrahydrofuran as the solvent medium.

EXAMPLE 6 Using a procedure analogous to that described in Example 2, 3.5 gm (81 percent of theory) of N-(2- methyl-3 -furylmethy1)- 14-hydroxy-7,8-dihydronorcodeinone hydrochloride, m.p. 272 C, were obtained from 3.37 gm (0.01 mol) of l4-hydroxy-7,8- dihydro-norcodeinone hydrochloride and 1.43 gm (0.011 mol) of 2-methyl-3-chloromethyl-furan with a mixture of 20 ml of tetrahydrofuran and 15 ml of dimethylformamide as the solvent medium.

EXAMPLE 7 Using a procedure analogous to that described in Example 2, 73 percent of theory of N-thenyl-l4-hydroxy- 7,8-dihydronorcodeinone hydrochloride, m.p. 259260 C, was obtained from 3.38 gm (0.01 mol) of 14-hydroxy-7,8-dihydro-norcodeinone hydrochloride and 1.45 gm (0.011 mol) of thenyl chloride.

EXAMPLE 8 Using a procedure analogous to that described in Example 2, 3.7 gm (85 percent of theory) of N-(3- thienyl-methyl)-14-hydroxy-7,8-dihydro-norcodeinone hydrochloride, m.p. 280-28l C, were, obtained from 3.38 gm (0.01 mol) of 14-hydroxy-7,8-dihydronorcodeinone hydrochloride and 1.95 gm (0.01 1 mol) of 3-bromomethyl-thiophene.

EXAMPLE 9 of tetrahydrofuran, 2.5 gm of sodium bicarbonate and 2.9 gm (0.011 mol) of 2-methyl-3-chloromethylfuran was refluxed for 4 hours, accompanied by stirring.

'Thereafter, the reaction solution was evaporated in vacuo, the residue was shaken with a mixture of 50 ml of chloroform and 50 ml of water and the aqueous phase was separated and extracted twice with 25 ml of chloroform each. The chloroform extracts were combined with the chloroform phase and the combined solution was dried with sodium sulfate and evaporated in vacuo. The residue was crystallized from a mixture consisting of ml of methanol and 50 ml of water, and the mixture was allowed to stand overnight. Thereafter, the crystalline substance was collected by vacuum filtaration, washed with aqueous methanol and dried, first in the air and finally at 80 C, yielding 4.2 gm (65 percent of theory) of the compound of the formula H3 C O 0 EXAMPLE 10 N-(S '-Methyl-furfuryl l 4-hydroxy-7,8-dihydronormorphinone by method B 3.24 gm (0.01 mol) of 14-hydroxy-7.8-dihydronormorphinone hydrochloride were dissolved in 10 ml of aqueous 50 percent acetic acid, the solution was admixed 1.1 ml of aqueous 30 percent formaldehyde (0.011 mol CH O) and 0.9 gm (0.011 mol) of 5- methyl-furan, and the resulting mixture was stirred for eight hours at room temperature. Thereafter, the reaction solution was evaporated in vacuo, the residue was shaken with a mixture consisting of 50 ml of chloroform, 50 ml of water and an excess of ammonia, and the aqueous phase was separated and extracted twice with ml of chloroform each. The chloroform extracts were combined with the chloroform phase,'and the combined solution was washed with water, dried with sodium sulfate and evaporated in vacuo. The residue, consisting of the raw reaction product, was chromatographically purified in an aluminum oxide column, as described in Example 1(a), and the purified base was crystallized from toluene and dried at 105 C, yielding 1.5 gm of N-(5-methylfurfuryl)-l4-hydroxy- 7,8-dihydro-normorphinone with a melting point of 180-l8l C which remained unchanged after recrystallization from toluene.

EXAMPLE ll 5 ml ofethanol by adding 2.5 N ethanolic hydrochloric acid thereto until just acid reaction. the acidic solution was admixed with absolute ether until it began to turn cloudy. and the mixture was allowed to stand overnight in a refrigerator. Thereafter, the crystalline precipitate was collected by vacuum filtration, washed first with ethanol/ether and then with only ether, and dried at 80 C, yielding 1.2 gm of crystalline N-(5'-methylfurfuryl)-l4-hydroxy-7,S-dihydro-norcodeine hydrochloride with a melting point of 204-205 C which did not change after recrystallization from ethanol/ether.

EXAMPLE l2 N-Furfuryll 4-hydroxy-7.8-dihydro-6,6-ethylenedioxydesoxynorcodeine by method C a. l4-HydroXy'7,8-dihydro-6,6-ethylenedioxydesoxynorcodeine and its hydrochloride A mixture consisting of 20.3 gm (0.06 mol) of l4- hydroxy-7,8-dihydro-norcodeinone hydrochloride. 80 ml of ethyleneglyeol and 2.3 gm of p-toluenesulfonic acid was heated for 2 hours at 80 C in a vacuum of 0.01 mm Hg. Thereafter, the reaction mixture was cooled and then stirred into 50 ml of 2 N sodium hydroxide, and the crystalline precipitate formed thereby was collected by vacuum filtration, washed several times with water and dried, first in the air and finally at C, yielding 17.5 gm (84.5 percent of theory) of 14- hydroxy-7,8-dihydro-6,o-ethylenedioxydesoxynorcodeine. m.p. 201 C.

2.0 gm of the free base thus obtained were dissolved in ethanol by adding the calculated amount of 2.5 N ethanolic hydrochloric acid thereto, and the resulting acidic solution was admixed with absolute ether until it just began to turn cloudy. Upon standing, a crystalline substance separated out which was collected by vacuum filtration, washed several times with water and dried, first in the air and finally at 80 C. yielding 2.0 gm of the hydrochloride of l4-hydroxy-7.8-dihydro- 6,6-ethylenedioxy-desoxynorcodeine with a melting point of 307 C which remained unchanged after recrystallization from ethanol/ether.

b. N-(2'-Furoyl)-l4-hydroxy-7,8-dihydro-6,6-

ethylenedioxy-desoxynorcodeine 6.9 gm (0.02 mol) of l4-hydroxy-7,8-dihydro-6,6- ethylenedioxy-desoxynorcodeine were dissolved in ml of methanol, and. while vigorously stirring the solution, it was admixed with a solution of 5 gm of potassium carbonate in 8 ml of water. While stirring the re sulting suspension, a total of 2.88 gm (0.022 mol) of furan-Z-carboxylic acid chloride were added thereto over a period of about 15 minutes in five portions, and the resulting mixture was stirred for one hour more. Thereafter, the reaction mixture was evaporated, the residue was shaken with a mixture consisting of 50 m1 of chloroform and 25 m1 of water, the aqueous phase was separated and again extracted with 25 ml of chloroform, the chloroform extract was combined with the chloroform phase, and the combined solution was washed in rapid succession with 25 ml of 2 N hydrochloric acid, 25 ml of water and 25 ml of l N sodium bicarbonate, all in the presence of ice. The washed solution was now dried with sodium sulfate and evaporated in vacuo, leaving as a residue raw N-(2'-furoyl)- l4-hydroxy-7,8-dihydro-6,o-ethylenedioxydcsoxynorcodeine. A small sample. recrystallized from aqueous methanol. had a melting point of 196 C.

c. The raw reaction product obtained under (b) was dissolved in 50 ml of absolute tetrahydrofuran. and the solution was added dropwise over a period of about 30 minutes to an ice-cooled suspension of 2.4 gm of lithium aluminum hydride in 30 ml of tetrahydrofuran, accompanied by stirring. Thereafter, the ice bath was removed, and the reaction mixture was stirred for 30 minutes more at room temperature and then refluxed for 2 hours. Subsequently, the reaction mixture was again placed on an ice bath and. while stirring, 6 ml of water were added dropwise and then it was admixed with ml of an aqueous saturated diammonium tartrate solution. The resulting mixture was now thoroughly shaken in a separating funnel. and then the tetrahydrofuran (upper) phase was separated and evaporated in vacuo. The aqueous phase was extracted once with 50 ml of chloroform and twice with 25 ml of chloroform each, the chloroform extracts were combined. the evaporation residue of the tetrahydrofuran phase was dissolved in the combined chloroform extracts. and the resulting solution was washed with water. dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from a mixture consisting of 45 ml of methanol and ml of water, and the crystallizate was collected by vacuum filtration, washed with a little aqueous methanol and dried, first in the air and finally at 80 C, yielding 7.5 gm (95 percent of theory, based on steps b and c) of N-furfuryl-l4-hydroxy-7,8- dihydro-6,6-ethylenedioxy-desoxynorcodeine, m.p. 92-94 C. After recrystallization from aqueous methanol the product had a melting point of 99 C.

EXAMPLE 13 N-(3'-Furyl-methyl)-l4-hydroxy-7,8-dihydro-6,6- ethylenedioxy-desoxynorcodeine by method C a. N-(3'-Furoyl)-l4-hydroxy-7,8-dihydronorcodeinone 20.3 gm (0.06 mol) of l4-hydroxy-7,8-dihydronorcodeinone hydrochloride were dissolved in 350 ml of methanol, and, while vigorously stirring the solution, it was admixed with a solution of 15 gm of potassium carbonate in 24 ml of water. While stirring the resulting suspension, a total of 8.7 gm (0.066 mol) of furan-3- carboxylic acid chloride were added in five portions thereto over a period of about 15 minutes, and the resulting mixture was stirred for 1 hour more. Thereafter, it was evaporated, the residue was shaken with a mixture consisting of 100 ml of chloroform and 50 ml of water, and the aqueous phase was separated and again extracted once with 50 ml of chloroform. The chloroform extract was combined with the chloroform phase, and the combined solution was washed in rapid succession with 50 ml of 2 N hydrochloric acid, 50 ml of water and 50 ml of 1 N sodium bicarbonate, all in the presence of ice. The washed solution was then dried with sodium sulfate and evaporated in vacuo, leaving 26.4 gm of raw, syrupy N-(3-furoyl)-14-hydroxy-7,8- dihydro-norcodeinone.

b. N-(3-Furoyl)-14-hydroxy-7,8-dihydro-6,6-

ethylenedioxy-desoxynorcodeine The raw reaction product obtained in step (a) was admixed with 100 ml of ethyleneglycol and 2.0 gm of p-tolulenesulfonic acid, and the mixture was heated for 2 hours at 80 C in a vacuum of 0.01 mm Hg. Thereafter, the reaction mixture was cooled and then stirred into a solution of 30 gm of sodium carbonate in 90 ml of water. The resulting mixture was extracted once with 100 ml of chloroform and twice with 50 ml of chloroform each, and the chloroform extracts were combined, washed with aqueous sodium carbonate, dried with sodium sulfate and evaporated in vacuo. The residue was crystallized from 80 ml of methanol, the mixture was allowed to stand overnight in a refrigerator, and the crystallizate was collected by vacuum filtration, washed with a little methanol, and dried first in the air and finally at 80 C, yielding 18.6 gm (73.5 percent of theory, based on steps a and b).of N-(3-furoyl)-14- hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynorcodenine, m.p. 162 C.

c. 9.3 gm (0.0212 mol) of the end product ofstep (b) were dissolved in 150 ml of absolute tetrahydrofuran, and the solution was added dropwise over a period of about 1 hour to an ice-cooled suspension of 2.6 gm of lithium aluminum hydride in 50 ml of tetrahydrofuran, accompanied by stirring. Thereafter, the ice bath was removed, and the reaction mixture was stirred for 1 hour at room temperature and the refluxed for 2 hours. The reaction mixture was worked up as described in Example 12(c), and the product was crystallized from ml of methanol and 15 ml of water, yielding 7.2 gm (80 percent of theory). of N-(3-furylmethyl)-l4- hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynorcodeine, m.p. 127 C. After recrystallization from aqueous methanol the compound had a melting point of 130 C.

EXAMPLE 14 Using a procedure analogous to that described in Example l2, 6.7 gm (79 percent of theory) of N-(3- methy1-furfuryl)-14-hydroxy-7,8-dihydro-6,o-ethylcnedioxy-desoxynorcodeine, m.p. 144 C, were obtained starting from 6.9 gm (0.02 mol) of 14-hydroxy-7,8- dihydro-6,6-ethylenedioxy-desoxynorcodeine and 3.2 gm (0.022 mol) of 3-methyl-furan-2-carboxylic acid chloride, followed by reduction of the intermediate N- (3 -methy1-2-furoyl)-14-hydroxy-7,8-dihydro-6,6- ethylenedioxydesoxynorcodeine (m.p. 223 C, from aqueous methanol) with lithium aluminum hydride.

EXAMPLE 15 Using a procedure analogous to that described in Example 12, 6.05 gm (71.5 percent of theory) of N-(2- methyl-3-furylmethyl)-14-hydroxy-7,8-dihydro-6,6- ethylenedioxy-desoxynorcodeine, m.p. C, were obtained starting from 6.9 gm (0.02 mol) of 14- hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynorcodeine and 3.2 gm (0.022 mol) of Z-methyl- 3-furoylchloride, followed by reduction of the intermediate N-(2-methyl-3-furoyl)-l4-hydroxy-7,8-dihydro- 6,6-ethylenedioxydesoxynorcodeine (m.p. 226 C, from aqueous methanol) with lithium aluminum hydride.

EXAMPLE 16 Using a procedure analogous to that described in Example 12, 6.4 gm (75 percent of theory) of N-thenyl- 14-hydroxy-7,8-dihydro-6,6-ethy1enedioxydesoxynorcodeine, m.p. 125 C, were obtained starting from 6.9 gm (0.02 mol) of l4-hydroxy-7,8-dihydro- 6,6-ethylenedioxy-desoxynorcodeine and 3.2 gm (0.022 mol) of thiophcne-2-carboxylic acid chloride, followed by reduction of the intermediate N-(2- thenoyl)-14-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynorcodeine with 2.4 gm oflithium aluminum hydride.

EXAMPLE 17 EXAMPLE l8 N-(3'-Furylmethyl)-14-hydroxy-7,8-dihydro-6,6-dimethoxydesoxynorcodeine by method C a. N-(3'-Furoy1)-14-hydroxy-7,8-dihydronorcodeinone In a manner analogous to that described in Example 13(a), 3.45 gm (0.01 mol) of l4hydroxy-7,8-dihydronorcodeinone hydrochloride were reacted with 1.44 gm of furan-3-carboxylic acid chloride, and the reaction mixture was worked up, yielding raw, syrupy N- (3'-furoyl)-14-hydroxy-7,8-dihydro-norcodeinone.

b. N-(3'-Furoy1)-14-hydroxy-7,8-dihydro-6,6-dimethoxy-desoxynorcodeine The raw reaction product obtained in step (a) was dissolved in 40 ml of absolute methanol, and the solution was admixed with 2 ml of 75 percent perchloric acid and ml of trimethylorthoformate. The resulting mixture was allowed to stand at room temperature for two hours and was then introduced into 150 ml ofa saturated aqueous sodium carbonate solution. The mixture was extracted three times with 50 ml of chloroform each, and the combined extracts were washed with water, dried with sodium sulfate and evaporated in vacuo, leaving as a residue raw N-(3'-furoyl)14- hydroxy-7,8-dihydro-6,6-dimethoxydesoxynorcodeine.

c. The end product of step (b) was reduced with 1.2 gm of lithium aluminumhydride and the reaction mixture worked up as described in Example 12(c), yielding the compound of the formula EXAMPLE 19 N-(3 -F urylmethy1)- l 4-hydroxy-7,8-dihydro-6,6-diethoxydesoxynorcodeine by method C Using a procedure analogous to that described in Example 18(11). 3.45 gm (0.01 mol) of l4-hydroxy'7,8- dihydronorcodeinone hydrochloride were reacted with 1.44 gm of furan-3-carboxylic acid chloride, yielding the intermediate N-(3-furoyl)-l4-hydroxy-7,8-dihydronorcodeinone.

The intermediate was ketalized in analogy to Example 18(b) with 40 ml of absolute ethanol, 2 ml of 72 percent perchloric acid and 20 ml of triethyl orthoformate, the reaction time being increased to 24 hours, to form N-(3'-furoyl)-l4-hydroxy-7,8-dihydro-6,6-diethoxy-desoxynorcodeine.

The ketalization product was then reduced with lithium aluminum hydride in analogy to Example 18(c), yielding 1.1 gm (24 percent of theory) of N-(3- furylmethyl)-14-hydroxy-7,8-dihydro-6,6-diethoxydesoxynorcodeine having a melting point of 118 C which did not change after recrystallization of the product from aqueous methanol.

EXAMPLE 20 N-Furfuryl-l4-hydroxy-7,8-dihydro-6,6- ethylenedioxy-desoxynormorphine by method C a. N-(2-Furoyl)-l4-hydroxy-7,8-dihydronormorphinone Using a procedure analogous to that described in Example l3(a), 9.75 gm (0.03 mol) of l4-hydroxy-7,8- dihydronormorphine hydrochloride were reacted in 200 ml of methanol in the presence of 7.5 gm of potassium carbonate and 12 ml of water with 4.3 gm of furan-Z-carboxylic acid chloride, and the reaction mixture was worked up, yielding 9 gm of syrupy N-(2'- furoy1)l4-hydroxy-7,8-dihydro-normorphinone. A sample thereof, recrystallized from ethyl acetate, had a melting point of 253 C.

b. N-(2-Furoy1)-l4-hydroxy-7,8-dihydro-6,6-

ethylenedioxy-desoxynormorphine A mixture consisting of 3.0 gm of the syrupy reaction product obtained in step (a), 15 ml of ethyleneglycol and 0.5 gm of p-toluenesulfonic acid was heated for 2 hours at C in a vacuum of 0.01 ml Hg. Thereafter, the reaction mixture was cooled and then introduced into a solution of 5 gm of sodium carbonate in 50 ml of water. The resulting mixture was extracted once with 50 ml of chloroform and twice with 25 ml of chloroform each, and the organic extracts were combined, washed with 25 ml of water, dried with sodium sulfate, and evaporated in vacuo, leaving as the residue raw N- (2-furoyl)-14-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine.

c. In analogy to Example 12(c), the raw reaction product obtained in step (b) above was reduced with 1.2 gm of lithium aluminum hydride, and the reduction product was isolated and crystallized from aqueous methanol, yielding 1.8 gm (43 percent of theory) of N- furfuryl-l4-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine having a melting point of 221 C which did not change after recrystallization from aqueous methanol.

EXAMPLE 21 Using procedures analogous to those described in Example 20(a), (b) and (c), 9.0 gm (55 percent of theory) of N-(3-furylmethyl)-l4-hydroxy-7,8-dihydro- 6,6-ethylenedioxy-desoxynormorphine. m.p. 235 C (238 C after recrystallization from aqueous methanol), were obtained from 13.0 gm (0.04 mol) of 14- hydroxy-7,8-dihydro-normorphinone hydrochloride.

EXAMPLE 22 N-(3'-Methyl-furfuryl)-14-hydroxy-7,8-dihydro norcodeinone and its hydrochloride by method D 3.7 gm (0.0087 mol) of N-(3-methyl-furfuryl)-l4- hydroxy-7,8dihydro-6,6-ethylenedioxydesoxynorcodeine (see Example 14) were refluxed in 50 ml of 2N hydrochloric acid for 30 minutes. Thereafter, the solution was allowed to cool and was then admixed with 15 ml of concentrated ammonia, and the resulting mixture was extracted three times with 25 ml of chloroform each. The combined organic extracts were washed with water, dried with sodium sulfate and evaporated in vacuo, and the residue, the free base N- 3 -methyl-furfuryl)- 1 4-hydroxy-7,8-dihydronorcodeinone, was dissolved in 40 ml of ethanol by addition of4 ml of 2.5 N ethanolic hydrochloric acid. The resulting solution was admixed with absolute ether until it just began to turn cloudy, the mixture was allowed to stand in a refrigerator overnight, and the crystallizate formed thereby was collected by vacuum filtration, washed first with ethanol/ether and then with only ether, and then dried first in the air and finally at 80 C, yielding 3.4 gm (90 percent of theory) of the hydrochloride of the formula having a melting point of 239 C, which remained unchanged after recrystallization from 50 ml of methanol, ml of water and 100 ml of ether.

EXAMPLE 23 N-(3'-Furylmethyl)-14-hydroxy-7,8-dihydronormorphinone and its hydrochloride by method D Using a three-step procedure analogous to that described in Example 20, 3.24 gm (0.01 mol) of 14- hydroxy-7,8-dihydro-normorphine hydrochloride were reacted with 1.44 gm of furan-3-carboxylic acid chloride, the reaction product was ketalized with ethylene glycol, and the ketalization product was reduced with 1.2 gm of lithium aluminum hydride to form N-(3- furylmethyl)-14-hydroxy-7,8-dihydro-6,6- ethylenedioxy-desoxynormorphine. Thus syrupy intermediate was then subjected to ketal cleavage with 2N hydrochloric acid in a manner analogous to that described in Example 22, and the cleavage product, N- (3-furylmethyl)-l4-hydroxy-7,8-dihydronormorphinone, was converted into its hydrochloride, isolated and crystallized. 2.2 gm (54.5 percent of theory) of the hydrochloride, m.p. 231 C, were obtained. The melting point reamined unchanged after recrystallization from ethanol/ether.

EXAMPLE 24 N-(2-Methyl-3-furylmethyl)-14-hydroxy-7,8-dihydronormorphinone by method D a. N-(2'-methyl-3-furylmethyl)-l4-hydroxy-7,8-

dihydro-6,6-ethylenedioxy-desoxynormorphine Using a three-step procedure analogous to that described in Example 20, 3.3 gm (0.01 mol) of 14- hydroxy-7,8-dihydro-6,6-ethylenedioxynormorphinone hydrochloride were reacted with 1.6 gm of 2-methyl-furan-3-carboxylic acid chloride, the reaction product was ketalized with ethyleneoxide, and the ketalization product was reduced with lithium aluminum hydride, yielding N-(2-methyl-3'-furylmethyl)- l4-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine as a syrupy residue.

b. The syrupy product obtained under (a) was subjected to ketal cleavage with 2 N hydrochloric acid in analogy to Example 22. The cleavage product, isolated by chloroform extraction, was crystallized from 250 ml of methanol and 100 ml of water, yielding 2.7 gm (71 percent of theory, based on steps a and b) of N-(2'- methyl-3'-furylmethyl)-14-hydroxy-7,8-dihydronormorphinone having a melting point of 229C; after recrystallization from 150 ml of methanol and ml of water it had a melting point of 230C.

EXAMPLE 25 Using a procedure analogous to that described in Example 24, 2.5 gm (65.5 percent of theory) of N-(3- methyl-fu rfuryl 1 4-hydr oxy-7,8-dihydronormorphinone, mp. 263C (crystallized from toluene), were obtained from 3.3 gm (0.01 mol) of l4 hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine. Recrystallization of the product from toluene did not change the melting point.

EXAMPLE 26 N-Thenyl-14-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine by method E A mixture consisting of 8.4 gm (0.02 mol) of N- thenyl-l4-hydroxy-7,8-dihydro-normorphinone hydrochloride (see Example 2), 30 ml of ethyleneglycol and 2.0 gm of p-toluenesulfonic acid was heated for 2 hours at C in a vacuum of 0.01 mm Hg. Thereafter, the reaction mixture was cooled and was then stirred into 40 ml of 2 N ammonia. The crystalline substance which separated out was collected by vacuum filtration, washed with water, and dried first in the air and finally at 80 C, yielding 6.6 gm (77 percent of theory) of N- thenyll 4-hydroxy-7,8-dihydro-6,6-ethylenedioxydesoxynormorphine with a melting point of 191 C which remained'unchanged after recrystallization from methanol/water.

EXAMPLE 27 N-(3.-Furylmethyl)-l4-acet0xy-7,8-dihydronorcodeinone and its hydrochloride by method F 2.7 gm (0.0645 mol) of N-(3-furylmethyl)l4- hydroxy-7,S-dihydro-norcodinone hydrochloride were shaken with a mimxture consisting of ml of chloroform and 50 ml of 2 N ammonia, and the chloroform phase was separated, washed with water, dried with sodium sulfate and evaporated in vacuo. The residue, the free base N-(3-furylmethyl)-14-hydroxy-7,8' dihydro-norcodeinone, was admixed with 9 ml of acetic acid anhydride, and the mixture was heated for 15 minutes on a boiling water bath and then evaporated in vacuo. The residue was shaken with 30 ml of chloroform and ice water while adding portions of ammonia thereto to restore the pH to 7; shaking and adding ammonia was continued until the pH remained at 7. The chloroform phase was now separated, washed with water, dried with sodium sulfate and evaporated in vacuo. The residue, the free base N-(3'-furylmethyl)-14- acetoxy-7,8-dihydro-norcodeinone, was dissolved in a little methanol by addition of ethanolic hydrochloric acid to pH 6, the solution was admixed with absolute ether until it just began to turn cloudy, and the mixture was allowed to stand overnight in a refrigerator. The crystalline substance which had separated out was collected by vacuum filtration and washed first with ethanol/ether and then only with ether, yielding 1.9 gm (61.5 percent of theory) of the hydrochloride of the formula I NCH1 0000 I a 3 0 O which had a melting point of 100103 C; it remained unchanged after recrystallization from methanol/ether.

EXAMPLE 28 Using a procedure analogous to that described in EX- ample 27, 3.1 gm (73 percent of theory) of N-furfuryl- 14-acetoxy-7,S-dihydro-norcodeinone, m.p. 202-203 C (203 Cfiffef r crystal1iza t iorif r 6rn erhana'n w'ere obtained from 4.2 gm (0.01 mol) of N-furfuryl-l4- hydroxy-7,8-dihydro-norcodeinone hydrochloride by crystallizing the evaporation residue of the chloroform extracts from ethanol.

EXAMPLE 29 Using a procedure analogous to that described in Example 27, 0.4 gm (71.5% of theory) of N-(3- furylmethyl -acetyll 4-acetoxy-7,8-dihydronormorphinone, m.p. 180 C, of the formula was obtained by converting 0.5 gm (0.00124 mol) of N-(3'-furylmethyl)-14-hydroxy-7.8-dihydronormorphinone hydrochloride into the free base, acetylating the latter with 5 ml of acetic acid anhydride, working up the reaction mixture as described in Example 27, and crystallizing the reaction product from isopropanol.

EXAMPLE N-(3-Furylmethyl)-l4-hydroxy-7,8-dihydro-6,6- propy1enedioxy-desoxynormorphine by method E A mixture consisting of 1.85 gm (0.005 mol) of N- (3'-furylmethyl)-14-hydroxy-7,8-dihydronormorphinone, 20 ml of absolute benzene, 1.0 gm of 1,3propyleneg1ycol and 1.72 gm of p-toluenesulfonic acid was refluxed for 4 hours while continuously removing the water released by the reaction by 21260- tropic distillation. Thereafter, the reaction solution was evaporated in vacuo, and the residue was purified by column chromatography on 200 gm of silicagel in a manner analogous to that described in Example 1 and crystallized from aqueous methanol. 1.2 gm (55 percent oftheory) of the compound named in the heading were obtained; it had a melting point of 223 C.

EXAMPLE 31" N-Thenyl-l4-7,8-dihydro-6,6-dimethoxydesoxynorcodeine by method E 1.7 gm (0.0033 mol) of NthenyI-l4-hytlroxy 7,8- dihydro-norcodeinone hydrochloride were dissolved in 16 ml of absolute methanol. and the resulting solution was admixed with 0.8 of 72 percent perchloric acid and 8.0 ml of trimethyl orthoformate. The mixture was allowed to stand at room temperature and under exclusion of moisture overnight, and was then poured into i 50 ml of an aqueous saturated sodium bicarbonate so lution. The resulting mixture was extracted three times with 25 ml of chloroform each, the combined extracts were washed with water, dried with sodium sulfate and evaporated in vacuo, and the residue was crystallized from a mixture of 20 ml of methanol and 5 ml of water. 1.1 gm (73.5 percent of theory) of the compound named in the heading were obtained; it had a melting point of 128 C, which was unchanged after recrystallization from aqueous methanol.

EXAMPLE 32 ethylenedioxy-desoxynormorphine The syrupy end product of step (a) was dissolved in 43 ml of absolute methylene chloride by addition of 1.62 ml of triethylamine, and the resulting solution was gradually admixed over a period of 15 minutes with a solution of 5.75 gm (0.044 mol) of furan-3-carboxylic acid chloride in 25 m1 of absolute methylene chloride, accompanied by stirring. The resulting mixture was refluxed for 4 hours, then cooled and subsequently, in the presence ofice, washed first twice with 20 ml of2 N hydrochloric acid each and then three times with 20 ml of water each. The organic phase was dried with sodium sulfate and evaporated in vacuo in a rotary evaporator, leaving 10.4 gm of a yellow oil.

c. O -(3-Furoyl)-N-(3"thiofuroyl)-l4-hydroxy-7,8- dihydro-6,6-ethylenedioxy-desoxynormorphine The oily end product of step (b) was dissolved in m1 of absolute pyridine, the solution was admixed with 2.56 gm of phosphorus pentasulfide, and the mixture was refluxed for 3 hours. Thereafter, the pyridine was removed in vacuo in a rotary evaporator, and the residue was shaken with a mixture of 100 m1 of methylene chloride and 100 m1 of wataer. The aqueous phase was separated and extracted with 50 m1 of methylene chloride, the organic extract was combined with the methylene chloride phase, and the combined solution was washed, in the presence of ice, first with 50 ml of 2 N hydrochloric acid and then three times with 30 m1 of water each, subsequently dried with sodium sulfate and evaporated in vacuo in a rotary evaporator, leaving 10 gm of a yellow oil.

(1. N-(3-Furylmethyl)-14-hydroxy-7,8-dihydro-6,6-

ethylenedioxy'desoxynormorphine 5.0 gm of the oily end product of step (e) were dissolved in 60 ml of absolute tetrahydrofuran, and the solution was added dropwise to an ice-cooled suspension of 0.76 gm of lithium aluminum hydride in 20 ml of absolute tetrahydrofuran, accompanied by stirring. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 30 minutes and subsequently refluxed for two hours. Thereafter, the

reaction solution was worked up as described in Example 12(c); the evaporation residue of the chloroform extracts was the desired product.

(e) The end product of step (d) was refluxed for 2 hours with 50 ml of 2 hydrochloric acid, the reaction mixture was allowed to cool and was the made alkaline with ammonia and extracted three times with 50 ml of chloroform each. The combined organic extracts were washed with water, dried with sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silicagel, as described in Example 1, and the purified base was converted into its hydrochloride and crystallized. 1.1 gm of N-(3'-furylmethyl)-l4- hydroxy-7,8-dihydro-normorphinone hydrochloride, m.p. 229230 C, were obtained; after recrystallization from a mixture of 25 ml of ethanol, 1 ml ofwater and 25 ml of ether the product had a melting point of 23023 1 C.

The compounds of the present invention, that is, those embraced by formula 1 above and their non-toxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, the compounds according to the present invention exhibit opiate antagonistic activities in warmblooded animals, such as mice and rats.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals perorally, enterally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective analgesic and antitussive dosage unit of the compounds according to the present invention is from 0.166 to 5.0 mgm/kg body weight, preferably 0.83 to 2.5 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 33 Tablets The tablet composition is compounded from the following ingredients:

N-Furfuryll 4-hydroxy-7.8-dihydro- Preparation:

The normorphinone compound is intimately admixed with the lactose and the corn starch, the mixture is moistened with an aqueous percent solution of the soluble starch, the moist mass is forced through a l mm-mesh screen, the resulting granulate is dried at 40 C, the dry granulate is admixed with the colloidal silicic acid, and the composition is compressed into 200 mgmtablets in a conventional tablet making machine. Each tablet contains 50 mgm of the normorphinone compound and is an oral dosage unit composition with effective opiate-antagonistic action.

XAM??? Coated pills The pill core composition is compounded from the following ingredients:

normorphinonc hydrochloride 75.0 parts Lactose 100.0 do. Corn starch 65.0 do. Colloidal silicic acid 2.0 do. Solublc starch 5.0 do. Magnesium stearate 3.0 do.

Total 250.0 parts Preparation:

The ingredients are compounded in the same manner as in Example 33, and the composition is compressed into 250 mgm-pill cores which are subsequently coated with a thin shell consisting essentially of a mixture of sugar, talcum and gum arabic and finally polished with beeswax. Each coated pill contains mgm of the normorphinone compound and is an oral dosage unit composition with effective opiate-antagonistic activity.

EXAMPLE 35 Suppositories The suppository composition is compounded from the following ingredients:

N-( 3'-Thicnylmethyl l 4-hydroxy-7,8-

dihydro-normorphinone hydrochloride 50.0 parts Lactose 250.0 do. Suppository base (cg. cocoa butter) 1400.0 do.

Total 1700.0 parts Preparation:

EXAMPLE 36 Hypodermic solution The solution is compounded from the following ingredients:

N-Furfuryll4-hydroxy-7.8-dihydronorcodeinone methanesulfonate 750 parts Sodium chloride 5.0 do.

Double-distilled water q.s.ac l 2000.0 do.

by vol.

Preparation:

The norcodeinone compound and the sodium chloride are dissolved in the double-distilled water. the solution is filtered until free from suspended particles,

' Preparation? 21 and the filtrate is filed under aseptic conditions into 2 cc-ampulcs which are subsequently sterilized and sealed. Each ampule contains 75 mgm of the norcodeinone compound, and its contents are an injectable dosage unit composition with effective opiate-antagonistic action.

E'xXMPL'ESf Drop solution The solution is compounded from the following ingredients:

dihydro-norcodcinone hydrochloride 0.70 parts Methyl p-hydroxy-benzoate 0.07 do. Propyl p-hydroxy-benzoate 0.03 do. Demineralized water q.s.ad 100.0 do.

wherein R is hydrogen, methyl or acetyl, R is hydrogen or acetyl, R is hydrogen or methyl, and 5 X is oxygen or sulfur,

or a non-toxic, pharmacologically acceptable acid ad dition salt there.

3. A compound of claim 1, which is of the formula NCH2{ j R;

OH X Q Q H(|) o d wherein R is hydrogen or methyl, and

X is oxygen or sulfur. or a non-toxic, pharmacologically acceptable acid addition salt thereof.

4. A compound of claim 1, which is of the formula acid addition salt thereof is substituted for the particular normorphinone or norcodeinone in Examples 33 through 37. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature ofthe inert pharamaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the inven tion or the scope of the appended claims.

We claim:

1. A compound of the formula R, is hydrogen, methyl or acetyl,

R is hydrogen or acetyl,

R is hydrogen or methyl,

Q is oxygen, dimethoxy, diethoxy, ethylenedioxy or propylene(l,3)dioxy, and

X is oxygen or sulfur, or a non-toxic, pharmacologically acceptable acid ad dition salt thereof.

2. A compound of claim 1, which is of the formula non-toxic, pharmacologically acceptable addition salt thereof.

8. A compound of claim 1, which is N-fiir fu ryl-M- hydroxy7,8-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.

9. A compound of claim 1, which is N-(3'- furylmethyl)-14-hydroxy-7,S-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof. i i 0 10. A compound of claim 1, which is N-(2'methyl- 3-furylmethyl)-14-hydroxy-7,S-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.

(5/69) UNITED STATES PATENT OFFICE CERTIFICATE OF CQRRECTION Patent No. 3,872,127 Dated M h 18, 1975 fi KLAUS STOCKHAUS HERBERT MERZ, ADOLF LANGBEIN GERHARD Y IALTHEE ggld Inventor(s) It is certified that error appears in the above-identified patent. and that said Letters Patent are hereby corrected as shown below:

Col. 1, line 8, "theinyl" should read thier lyl Col. ll, line L1 "tolulene" should read ,toluene Col. 16, line "mi'mxture" should read mixture Col. 17, line hydroxy should be inserted after "'1 P" Col. 21, .line 1, "filed should read--'- filled---- Signed and Scaled this sixteenth D 3) 0f March 1976 [SEAL] A ttes t:

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner uj'Parents and Trademarks UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. q 379 197 Dated 3 g 7 Invent Herbert M e LZ l a It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Signed and Scaled this sixteenth Day of March 1976 [SEAL] Attest.

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner of Patents and Trademarks of0.76 gm oflithium aluminum hydride in 20 ml of absolute tetrahydrofuran, accompanied by stirring. The ice bath was then removed, and the reaction mixture was stirred at room temperature for minutes and subsequently refluxed for two hours. Thereafter. the

reaction'solution was worked up as described in Example 12(c); the evaporation residue of the chloroform extracts was the desired product.

(e) The end product of step (d) was refluxed for 2 hours with 50 ml of 2 N hydrochloric acid. the reaction mixture was allowed to cool and was the made alkaline with ammonia and extracted three times with 50 ml of chloroform each. The combined organic extracts were washed with water. dried with sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silicagel, as described in Example l. and the purified base was converted into its hydrochloride and crystallized. 1.] gm of N-(3'-furylmethyl)-l4- hydroxy-7,8-dihydro-normorphinone hydrochloride, m.p. 229-230 C, were obtained; after recrystallization from a mixture of25 ml of ethanol. 1 ml ofwater and 25 ml of ether the product had a'mel'ting point of 23023 l C. v

The compounds of the present invention, that is, those embraced by form ula' l above and their non-toxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, the-compounds according to the present invention e'xhibitopiate'antagonistic activities in warm-' blooded animals, suchas mice and rats.

For pharmaceutical purposes the compounds according to the present invention are administered to warm-' blooded animals perorally, enterally or parenterally as active ingredients in customarydosage unit compositions. that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient,-such as tablets. coated pills, capsules, wafers. powders, solutions, suspensionsyemulsions, syrups. suppositories and the like. One effective analgesic and antitussive dosage unit of the compounds according to the present invention is from 0. I66 to 5.0 mgm/kg body weight, preferably 0.83 to 2.5 mgm/kg body weight.

The following examples illustrate a few pharmaceuti-.

cal dosage unit compositionscomprising a compound of the present invention as an active ingredient and represent the best modes contcmplated of putting the inunless otherwise specified.

EXAMPLE 33 Tablets I v The tablet composition is compounded: from the following ingredients:

normorphinone by rochlori e 50.0 parts Lactose 95.0 do. Corn starch 45.0 do. Colloidal silieic acid 1.0 do. Soluble starch 5.0 do. Magnesium stcamte 3.0 do.

2000 parts Total Preparation:

vention into practical use. The partsare partsbyweight mm-mesh screen. the resulting granulate is dried at 40 C. the dry granulate is admixed with the colloidal silicic acid. and the composition is compressed into 200 mgmtablets in a conventional tablet making machine. Each tablet contains mgm of the normorphinone compound and is an oral dosage unit composition with effective opiate-antagonistic action.

EXAMPLE 34 Coated pills The pill core composition is compounded from the following ingredients:

normorphinonc hydrochloride 75.0 parts Lactose 100.0 do. Corn starch 65.0 do. Colloidal silicic acid 2.0 do. Soluble starch 5.0 do. Magnesium stearate 3.0 do

EXAMPLE 35 Suppositories The suppository composition is compounded from the following ingredients: I

dihydro-normorphintme ydrochloride 50.0 parts Lactose 250.0 do. Suppository base leg. cocoa butter) l400.0 do.

Total I 700.0 parts Preparation The normorphinone compound is intimately admixed with the lactose, and the mixture is blended with the aid of an immersion homogenizer into the suppository base which had previously been melted and cooled to about 40 C. 1,700 mgm-portions of the compositions are poured into cooled suppository molds and allowed to harden therein. Each suppository contains 50 mgm of the normorphinone compound and is a rectal dosage .unitcomposition with effective opiate-antagonistic action.

EXAMPLE 36 hypodermic solution The solution is compounded from the following ingredients:

75.0 parts norcodeinonc methanesulfonate Sodium chloride I 5.0 do. D\illblt.dili" -d \vatcr q.s-.ad 2000.0 do.

' by vol.

Preparation:

The norcodeinone compound and the sodium chlo- -ride. are dissolved in the double-di$tilled water. the solution 'is filtered until free from suspended particles. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, which is of the formula
 3. A compound of claim 1, which is of the formula
 4. A compound of claim 1, which is of the formula
 5. A compound of claim 1, which is N-furfuryl-14-hydroxy-7,8-dihydro-normorphinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 6. A compound of claim 1, which is N-thenyl-14-hydroxy-7,8-dihydro-normorphinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 7. A compound of claim 1, which is N-(3''-thienylmethyl)-14-hydroxy-7,8-normorphinone or a non-toxic, pharmacologically acceptable addition salt thereof.
 8. A compound of claim 1, which is N-furfuryl-14-hydroxy-7,8-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 9. A compound of claim 1, which is N-(3''-furylmethyl)-14-hydroxy-7,8-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 10. A compound of claim 1, which is N-(2''-methyl-3''-furylmethyl)-14-hydroxy-7,8-dihydro-norcodeinone or a non-toxic, pharmacologically acceptable acid addition salt thereof. 